Method of administering aldohexoseurea hypoglycemic compounds to animals



United States Patent METHOD OF ADMINESTERWG ALDOHEXOSE- UREA HYPOGLYCEMIC (IOMEOUNDS T0 ANIMALS Howard d. Clark, St. .leseph, llL, assignor to Universal Drug and Research Laboratories, Inc, a corporation of lt'llinois No Drawing. Filed Feb. 6, 1961, er. No. 37,121 8 Claims. (Cl. 16755) This invention relates to a method for reducing the blood sugar in animals. The primary objects of the invention are to provide a hypoglycemic agent which may be administered orally, which remains stable over long periods of time without refrigeration, which may be administered in either the solid or liquid state, and which produces a sustained response.

I have found that remarkable reduction in blood sugar can be produced by administering a compound taken from the group consisting of hexosyl ureas and esters thereof. This group is intended to embrace particularly the monoand diglucosyl ureas. There has been some speculation as to whether the monoglucosyl ureas are cyclical or straight chain compounds. The diglucosyl ureas are generally conceded to be glucopyranosyl ureas having the ring structure. Hexosyl ureas may be prepared by reacting an aldohexose (any of the stereoisomers) with urea. The compounds resulting from this reaction have been described in the literature (Benn, M. N., and Jones, A. 8., Chem. and Ind. 1959, 997; Segal et al., I. Am. Chem. Soc. 82, 2807). The compounds particularly useful as hypoglycemic agents are those which utilize the d-glucose, d-mannose and d-galactose isomers as the aldohexose. d-Glucose, for example, reacts with urea to form 1,3 bis-d-glucopyranosyl urea (diglucosyl urea) having the following structural formula:

OIIzOH O These hydroxy compounds may be esterified by reacting with an organic acid to produce esters having one or more OH groups esterified. These esters have also been found to be suitable for purposes of the invention. Fatty acid esters such as the stearates, palmitates and oleates of the hexosyl ureas particularly have been found to produce the desired hypoglycemic activity. The esters have substantially the same efiect as the unsubstituted base compounds, but usually must be administered in larger doses.

These hexosyl urea compounds have been administered in quantities generally ranging from 0.5 to 7.5 milligrams per kilogram of body weight. The quantity, of course, will have to be adjusted in each individual case after a clinical study of the patient and in conjunction with the regulation of the patients diet. The amount at which a hyperglycemic effect is produced will vary with the individual and cannot be absolutely defined.

The following specific examples will illustrate the effect of the compounds of the invention in reducing the blood sugar. The tests were made on diabetic dogs rendered diabetic in some cases surgically by removing the pancreas and in other cases chemically by alloxan administration. In the data set forth in the specific examples the blood sugar is measured in milligrams per 100 cubic centimeters (mg. percent) on samples taken in the morning after overnight fasting. During the tests on the compounds of the invention the animals were on insulin in sufiicient quantities to keep them alive, but in insufficient quantities to keep them in a normally healthy state with insulin alone. The insulin was injected after the blood sample was taken and before the morning feeding. The dogs were fed twice daily, morning and night. The compound of the invention was administered orally just before the evening feeding on the day indicated. Hence the blood test is not affected by the medication on the day of administration but on the day following.

Example I A surgically diabetic dog weighing 11 pounds and identified as Dog No. 16 was given 25 mg. (approximately 5 mg. per kg.) of the stearic acid ester of 1,3-bis-dglucopyranosyl urea (hereinafter referred to as diglucosyl urea stearate). On the day the drug was administered the blood sugar content of the animal was 373 mg. The next morning the sugar was reduced to 338 mg. and on the second day without further medication the sugar went down to mg. On the third day after the original administration of 25 mg. of diglucosyl urea stearate the blood sugar rose to 337 mg, whereupon an additional 25 mg. of the stearate Was administered. Once again the blood sugar count went down to 103 mg. On the fourth day without further medication the blood sugar returned to the higher level of 446 mg, thus confirming the initial response of this animal to the action of the drug. In the evening of the fourth day another dose of the drug was administered in the amount of 25 mg. The next morning, the fifth day, the blood sugar went down to 264 mg. That evening the second con secutive dose was administered. The following morn ing, the sixth day, the blood sugar was 84 mg. On the evening of the sixth day the third consecutive dose was administered and the following morning, the seventh day, the blood sugar had risen to 281 mg, a typical hyperglycemic response to an excess of the drug. It is to be noted that this hyperglycemic response was obtained rather than a hypoglycemic coma from an excess of medication. Accordingly the medication was discon tinued. Nevertheless, on the morning of the eighth day the blood sugar had risen further to 386. The following morning, the ninth day, it began its descent and was down to 338. From the tenth through the twelfth days no tests were made to determine blood sugar. But the blood sugar continued its descent and on the thirteenth day had gone down to 153 mg, on the fourteenth day to 97, on the fifteenth day to 84, on the sixteenth day 144, and on the seventeenth day 167, without any medication whatsoever after the three consecutive doses.

It will be observed that as the excess drug was excreted the optimum concentration was passed through and the blood sugar remained at acceptable values for about eight consecutive days.

On the eighteenth day the blood sugar again rose to 348, whereupon an additional 25 mg. of diglucosyl urea palmitate was administered. The next morning, the nineteenth day, the blood sugar had gone down to 100. On the twentieth day the blood sugar rose to 372 mg, thus indicating the response to a single dose of the palmitate.

Example 11 A surgically diabetic dog weighing 30 pounds identified as Dog A was treated with diglucosyl urea in the quantity of 34 mg. (2.5 mg. per kg.) on the evening of the day when the morning blood sugar stood at 361 mg. 0n the morning of the next day, the first, the blood sugar had risen to 373 mg. and on the second and third days went down to 265 and 233 mg. respectively. No readings are available for the fourth and fifth days. On the sixth day the reading was 248 and on the seventh day it rose to 347, whereupon 34 mg. of diglucosyl urea stearate was administered. This was for the purpose of comparing directly the effect of diglucosyl urea and its stearic acid ester. The blood sugar on the eighth day dropped to 289 and without further administration of the drug the sugar content rose to 396 on the ninth day. It will be apparent from the data that this dog showed a nice response, once to diglucosyl urea and another time to diglucosyl urea stearate.

Example 111 A surgically diabetic dog weighing 23 pounds and iden tified as Dog No. 20 was given 26 mg. (2.5 mg. per kg.) of diglycosyl urea on a day when his blood sugar stood at 290 mg. The following morning, the first day, the sugar had risen slightly to 295 mg. and, without further medication, on the morning of the second day the blood sugar had fallen to 237 mg. On the third and fourth days the sugar rose to 316 and 360 mg. respectively, whereupon a second dose of hypoglycemic agent was administered. This time diglucosyl urea stearate was administered in a quantity of 26 mg. The next day, the fifth, the blood sugar remained at 360, on the sixth day it had gone down to 289, and on the seventh and eighth days had risen to 316 and 320, respectively. Thus we see that this diabetic dog responded to both drugs.

Example IV An alloxan diabetic dog weighing 22 pounds and identified as Dog No. 7 was treated with 25 mg. mg. per kg.) of diglucosyl urea on a day when its blood sugar was 307 mg. On the next morning, the first day after the drug was administered, the blood sugar had fallen to 273, and one day later, the second day, it remained at 273 without further medication. The third day the blood sugar was still further reduced to 252. On the fourth day there was an increase to 266, whereupon 25 mg. of diglucosyl urea stearate was administered. On three successive days (the fifth, sixth and seventh) after this second administration the blood sugar read 266, 237 and 207. On the eighth day it returned to 285 mg.

Example V A surgically diabetic dog weighing 35 pounds identified as Dog C was treated once only with 30.7 mg. (1.9 mg. per kg.) of diglucosyl urea when his blood sugar stood at 398 mg. The next morning, the first day, the blood sugar was lowered to 205. One day later, the second day, it stood at 180, the third day 235, the fourth day 207, the fifth day 266, the sixth day 231, and the seventh day 121. On the eighth day the blood sugar returned to 336, indicating completion of the cycle. This dog, it will be noted, showed a prolonged response of seven days to a single administration of diglucosyl urea.

Example VI A surgically diabetic dog weighing 19 pounds identified as Dog No. 17 was treated with 8.6 mg. (1 mg. per kg.) of diglucosyl urea when his blood sugar stood at 336 mg. The next morning, the first day, the blood sugar had descended to 152 mg. That evening a like amount was administered and the following morning, the second day, the blood sugar had descended to 90 mg. For the next seven days, i.e., from the third through the ninth days, a like quantity of diglucosyl urea was administered daily in the evening before the evening feeding. The blood sugar on those days was 140, 121, 152, 117, 108, 153 and 176, respectively. At this time the medication was discontinued. 011 the tenth day the blood sugar still stood at 162 mg, without further medication on the eleventh day the blood sugar stood at 176 mg, and on the twelfth and thirteenth days at 298. On the evening of the thirteenth day 8.6 mg. (1 mg. per kg.) of monoglucosyl urea was administered and on the next morning, the fourteenth day, the blood sugar had risen to 447 mg. That evening a like amount of the monoglusosyl urea was administered and the following morning, the fifteenth day, the blood sugar had descended to mg. That evening a like amount of the drug was administered and on the followingmorning, the sixteenth day, the blood sugar rose to 348 mg. Without further medication, on the seventeenth day the blood sugar rose to 448 mg.

It will be noted that the animal was essentially under control -for a period of approximately eleven days following the administration of daily doses of diglucosyl urea. The data also indicates that there was a good response to the administration of monoglucosyl urea.

Example VII An alloxan diabetic dog weighing 16 pounds and identified as Dog No. 5 was treated with 7.3 mg. (1 mg. per kg.) of monoglucosyl urea when his blood sugar stood at 328. The following morning, the first day, the blood sugar had descended to 103. On the second day, without further medication, the blood sugar had returned to 191, and on the third day it went down to 78 without further medication.

I claim:

1. A method for lowering the blood sugar in animals which consists in orally administering a compound taken from the group consisting of the reaction product of an aldohexose stereoisomer and urea and fatty acid esters thereof.

2. A method for lowering the blood sugar in animals which consists in orally administering a compound taken from the group consisting of the reaction product of an aldohexose stereoisomer and urea and fatty acid esters thereof in an amount ranging from 0.5 to 7.5 milligrams per kilogram of body weight.

3. A method for lowering the blood sugar in animals which consists in administering orally a quantity of 1,3 bis-d-glucopyranosyl urea.

4. A method for lowering the blood sugar in animals which consists in orally administering a fatty acid ester of the reaction product of an aldohexose stereoisomer and References Cited in the file of this patent UNITED STATES PATENTS Opplt Nov. 16, 1954 Richter et al May 21, 1957 OTHER REFERENCES Benn et al.: Chemistry and Industry, August 1, 1959,

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 149,033 September 15 196? Howard S. Clark It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

In the heading to the printed specification lines 2 to 4, title of invention, for "METHOD OF ADMINISTERING ALDOHEXOSE-UREA HYPOGLYCEMIC COMPOUNDS TOANIMALS read METHOD FOR LOWERING BLOOD SUGAR IN ANIMALS BY USE OF ALDOHEXOSE-UREA COMPOUNDS Signed and sealed this 9th day of February 1965,

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A METHOD FOR LOWERING THE BLOOD SUGAR IN ANIMALS WHICH CONSISTS IN ORALLY ADMINISTERING A COMPOUND TAKEN FROM THE GROUP CONSISTING OF THE REACTION PRODUCT OF AN ALDOHEXOSE STEREOISOMER AND UREA AND FATTY ACID ESTERS THEREOF. 